Reciprocal Regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome Is Required for Genomic Stability during Mitotic Stress

• Published in: Cell reports (Cambridge) 2017-02, Vol.18 (8), p.1982-1995
• Main Authors: Kucharski, Thomas J., Minshall, Paul E., Moustafa-Kamal, Mohamed, Turnell, Andrew S., Teodoro, Jose G.
• Format: Article
• Language: English
• Subjects: 53BP1; Anaphase-Promoting Complex-Cyclosome - metabolism; anaphase-promoting complex/cyclosome; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Genomic Instability - genetics; HEK293 Cells; HeLa Cells; Humans; mitosis; Mitosis - genetics; Spindle Apparatus - metabolism; spindle poison; Tumor Suppressor p53-Binding Protein 1 - metabolism; ubiquitin; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.01.080

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1. [Display omitted] •53BP1 is an anaphase-promoting complex/cyclosome substrate in early mitosis•53BP1 interacts with the APC/C co-activators via its KEN boxes and tBRCT domain•53BP1 inhibits the APC/C in vivo and in vitro•53BP1 silencing results in extreme sensitivity to mitotic poisons Kucharski et al. find that 53BP1 is a mitotic APC/C substrate and an interphase inhibitor. 53BP1 silencing leads to a hyperactive APC/C, resulting in cell cycle defects and sensitivity to mitotic poisons. This helps to explain observations that 53BP1 null mice display aneuploidy and cancer susceptibility.